The primary goal of this research is to gain novel insights into how Interleukin (IL)-33 and the IL 33 receptor are involved in the pathogenesis of atopic dermatitis, an often-debilitating inflammatory disease of the skin that affects over ten million Americans, including Veterans. Cytokines are an important class of inflammatory proteins produced by many cell types including keratinocytes. Interleukin 33 is a cytokine produced by keratinocytes and other cell types and is implicated in atopic dermatitis and another common inflammatory disease of the skin, psoriasis. Unlike most cytokines, IL-33 also has intracellular functions in the nucleus where it may regulate gene expression. This work will evaluate the mechanism(s) by which IL-33 and the IL-33 receptor regulate the atopic dermatitis-like phenotype in Stat6VT transgenic mice, a T cell-dependent mouse model of disease. These studies will also be extended to involve patients with atopic dermatitis and psoriasis. Use of T1/ST2 (i.e. the ligand-specific subunit of the IL-33 receptor) knockout mice will help determine if the immunoregulatory effects of IL-33 on the atopic dermatitis-like phenotype in Stat6VT mice are mediated by the IL-33 receptor. Adoptive transfer experiments will be performed to determine if regulatory T cells contribute to immunoregulation of the atopic dermatitis-like phenotype in Stat6VT mice in an IL-33 receptor-dependent manner. Skin-derived CD4+ T cells from patients with atopic dermatitis and psoriasis (and healthy controls) will be isolated to study the impact of IL-33 on effector cytokine production by these cells. The roles of IL-33 and the IL-33 receptor in epidermal barrier function and keratinocyte differentiation will be evaluated using IL-33 and T1/ST2 knockout mice. Similar studies will be performed with using human keratinocytes in which IL-33 and IL-33 receptor expression are modulated using lentiviral systems to force and/or attenuate expression of IL-33 and T1/ST2. In conclusion this project is designed to advance the understanding of how IL-33 and the IL- 33 receptor are involved in atopic dermatitis and extend our studies to psoriasis, two of the most common inflammatory diseases of humans. The ultimate goal of these investigations is to identify novel therapeutic targets to improve treatments of these and other common inflammatory diseases of the skin thereby improving healthcare for Veterans and other patient populations.